These experiments address the problem of congestive cardiomyopathy at two levels: firstly, they investigate the rate of myocell loss, replacement fibrosis and compensatory hypertrophy of remaining myocytes in the genesis of progressive ventricular failure; secondly, they approach the mechanism(s) by which groups of myocytes undergo necrosis while leaving genetically identical cells unaffected. Previous studies from our laboratories have demonstrated significant abnormalities of sympathetic tone in these animals, which together with observations of preventable microvascular spasm may be the major determinant of myocellular necrosis. In contrast to previous hypotheses regarding the etiology of the cardiomyopathies, the concept of "microvascular" spasm is testable and has enormous potential for preventative therapy. In addition to hamster and hypertensive-diabetic cardiomyopathies, the cardiomyopathies associated with pheochromocytoma, intracranial bleeding, the collagen-vascular diseases (especially systemic lupus and progressive systemic sclerosis) have similar light microscopic pathology. Hypertrophic obstructive cardiomyopathy may fall into this category as well. Theoretically microvascular spasm, by leading to the loss of myocytes, should result in an increased load on the remaining cells with compensatory hypertrophy in these cells; ultimately this would lead to final cardiac decompensation, failure and death. Factor and others, as described in the body of the grant, have shown that calcium antagonists may be preventative. In addition to investigation of this hypothesis, this proposal integrates other significant approaches that will provide data concerning the primary or secondary role of contractile protein abnormalities, proteolytic enzyme activity, genetic alterations and the affect of interstitial scarring on the development of cardiomyopathy. Studies of skeletal muscle contractile mechanisms will establish correlative data useful for understanding the cardiac disease in these animals. The integrated and multifacetted approach of this proposal gives us a unique opportunity to determine the pathogenesis of cardiomyopathy in the Syrian hamster; and with the additional knowledge gained from studying the effect of preventive therapy may allow us to apply these lessons to human cardiomyopathies.